Project Summary According to the developmental origins of health and disease hypothesis, many disorders originate via environmental exposures in fetal and early postnatal life. Such early life environmental exposures can alter the developmental trajectory by disrupting the homeostasis of one or more systems, and in doing so produce identifiable biochemical signatures characteristic of the disease process or outcome. However, the lack of a conceptual framework as well as technological barriers have hampered research in this area; consequently, many disorders are not detected until overt clinical signs appear in adulthood, at which point it is no longer possible to meaningfully alter the course of development or disease. We are proposing a new paradigm that will overcome these barriers to detect disease years before current clinical and biochemical tests. By doing so we will be able to predict, and even prevent and treat diseases decades before any clinical signs. Central to our proposal is an underappreciated characteristic of many human physiologic processes?they commonly exhibit highly temporally resolved biochemical rhythms (or cycles) when at homeostasis. The idea of biochemical rhythms in itself is not revolutionary; sleep cycles, body temperature, cortisol rhythms, and menstrual cycles are all examples of the rhythmic nature of human physiology operating at various intervals. Medical testing, however, seldom considers rhythmicity. We propose to develop not just a novel technology that analyzes dynamic rhythmicity of key biochemical pathways during fetal development and childhood to accurately detect marked and sustained deviations from homeostasis that would be prognostic of later-life disease onset, but also a new framework for understanding development not solely as a linear trajectory but as interconnected rhythmic processes embedded within the growth trajectory.